018 - Observations on Prophylactic Inoculation Against Pneumococcus Infections, and on the Results Which Have Been Achieved by It.

Now for the study that preceeded that of my last post (017) because I encountered that one before this one: this one was by the famous Almroth E. Wright who developed the typhoid vaccine and hated biostatistics. He undertook a fairly large vaccination program against pneumococcal pneumonia in South African mining camps.¹

Actually he tried vaccine therapy as well, but it didn’t work very well, so he could not recommend its practice. But the prophylactic  use of vaccines seemed much more effective. The study described 6 mass experiments of mining workers, each with a slightly-to-very different purpose.

In all of them, a vaccine made of killed pneumococci was injected into subjects.

The first was a study of 11634 men, about half of whom were vaccinated. These were enrolled and vaccinated, then hung around the camp for about a month, and then headed off to the mines. In that month, about 2.6% of the vaccinated and 3.5% of the unvaccinated caught pneumonia, and 83 out of 10,000 vaccinated vs. 153 out of 10,000 unvaccinated died. In total in the first 2 months after vaccination (one month in camp and one in mines), 1% of vaccinated and 2% of unvaccinated died of pneumonia. After the second month, the difference between groups was not so great; the number of cases in the unvaccinated group decreased until it was about the same as the vaccinated.

The second studied as many as 30,000 subjects, but the record-keeping was so bad that the data was unusable. Hopefully it helped some people survive pneumonia though. In the third, about 10,000 men were vaccinated and another 10,000 not, and vaccination reduced the morbidity (number of cases) from 2.05% to 1.1% and the mortality (number of deaths) from 38 in 10,000 to 21 in 10,000.

The fourth mass experiment was smaller but mainly similar to the first three; I’m not sure what set it apart. But the fifth was intended to determine the optimum dosing and growth medium for vaccine preparation, in which the authors found that they had been giving too small a dose. In terms of side effects, none of the doses produced worse side effects than a slight fever and malaise. So for the 6th experiment they increased the dose.

So in the sixth, there was a reduction in mortality of about 60%, from 1.77% unvaccinated dying to 0.7% vaccinated dying, and this was the best result of the six experiments. There is a summary table showing the trend in the camps over the three years this study occupied; as higher proportions of workers were vaccinated, the incidence, death rate, and number of working days lost decreased.

 The authors speculated that the decline in the difference between vaccinated and unvaccinated after the first 2 months could be due to the latter population gaining some natural immunity to the disease, rather than the former losing their protection, and that idea does seem to have some merit. They also point out that it’s quite possible that the rates of pneumonia in unvaccinated workers could be lower than they would be if not for the 50-90% of the population that were vaccinated; in a sort of herd immunity, the presence of vaccinated individuals could limit the spread of disease among the unvaccinated.

However, there are significant limitations to this study, as later reviews point out.  For example, the study I reviewed in the previous post points out that Wright neglected to distinguish between different strains of pneumococcus in his vaccine, thus confusing the interpretation.²

Other criticisms:

"Unfortunately, the results he obtained with pneumococcal vaccine did not convince the scientific community of its efficacy. The problem lay in the failure to include both pneumococcal serotypes known at that time and in the use of an inadequate vaccine dosage because of the discomfort associated with the injection of relatively large inocula of whole killed pneumococci."³

"Although the results of these trials indicated that the vaccine could prevent pneumonia, the many flaws in design, particularly the lack of statistical soundness and microbiological evaluations, precluded any conclusions."⁴

"The vaccines employed were of unknown composition with regard to the pneumococcal type or types included in them, and in retrospect contained too few organisms to be fully immunogenic to man. Although Wright, who had a profound antipathy toward biostatistics, concluded that the trials demonstrated the efficacy of vaccination, careful analysis of his data provides little support for this view."⁵

So overall, the results are not great, even compared to the study in my previous post. But better seems yet to come.

1. Wright, A., Parry Morgan, W., Colebrook, L. & Dodgson, R. W. Observations on Prophylactic Inoculation Against Pneumococcus Infections. and on the Results Which Have Been Achieved by It. The Lancet 183, 87–95 (1914).

2. Cecil, R. L. & Austin, J. H. Results of prophylactic inoculation against pneumococcus in 12,519 men. J. Exp. Med. 28, 19–41 (1918).

3. Watson, D. A., Musher, D. M., Jacobson, J. W. & Verhoef, J. A Brief History of the Pneumococcus in Biomedical Research: A Panoply of Scientific Discovery. Clin. Infect. Dis. 17, 913–924 (1993).

4. Bruyn, G. a. W. & Furth, R. van. Pneumococcal polysaccharide vaccines: Indications, efficacy and recommendations. Eur. J. Clin. Microbiol. Infect. Dis. 10, 897–910 (1991).

5. Austrian, R. The Development of Pneumococcal Vaccine. Proc. Am. Philos. Soc. 125, 46–51 (1981).